Download Hindbrain noradrenergic A2 neurons: diverse roles in autonomic

Am J Physiol Regul Integr Comp Physiol 300: R222–R235, 2011.
First published October 20, 2010; doi:10.1152/ajpregu.00556.2010.
Review
Hindbrain noradrenergic A2 neurons: diverse roles in autonomic, endocrine,
cognitive, and behavioral functions
Linda Rinaman
Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania
Submitted 24 August 2010; accepted in final form 13 October 2010
catecholaminergic; dorsal vagal complex; nucleus of the solitary tract; stress;
visceral
THE MAMMALIAN BRAIN STEM CONTAINS several distinct groups of
noradrenergic (NA) neurons that were initially described by
Dahlström and Fuxe (59) who labeled the groups A1 through
A7 as they extend from the caudal ventrolateral medulla
through the rostral lateral pons. NA neurons collectively
project throughout the central nervous system and are broadly
implicated in behavioral and physiological processes related to
attention, arousal, motivation, learning and memory, and homeostasis. NA neurons are distinguished by positive immunolabeling for tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine synthesis, and dopamine-␤-hydroxylase
(DbH), the enzyme that converts dopamine to norepinephrine
(NE) (8). Conversely, neurons comprising the A1-A7 cell
groups are not immunopositive for phenylethanolamine Nmethyltransferase (PNMT). PNMT catalyzes the synthesis of
epinephrine from NE, and its presence is used to identify
adrenergic neurons of the C1-C3 cell groups (59).
This review focuses on the A2 cell group, a fascinating
collection of NA neurons contained within the dorsal vagal
complex (DVC) in the caudal dorsomedial medulla (see Fig. 1). As
Address for reprint requests and other correspondence: L. Rinaman, Dept. of
Neuroscience, Univ. of Pittsburgh, A210 Langley Hall, Pittsburgh, PA 15260
(e-mail: [email protected]).
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discussed further, below, the intra-DVC location of A2 neurons
supports their known involvement in vagal sensory-motor
reflex arcs and vagal motor outflow to multiple visceral targets.
Perhaps less well appreciated is the role of A2 neurons in
processes as diverse as satiation, sickness behavior, affective
state, endocrine and behavioral stress responses, immune-tobrain signaling, emotional learning, memory consolidation,
and addictive drug dependence. A2 neurons participate in
reciprocal connections between the visceral DVC and other
medullary, pontine, diencephalic, and telencephalic brain regions that underlie these diverse processes. Direct projections
from the cortex, limbic forebrain, and hypothalamus to the
region of the A2 cell group provide a route through which
emotional and cognitive events can modulate visceral responses to diverse threats and opportunities to which the
organism is exposed, including conditioned responses that are
based on past experience (193, 225). In turn, ascending projections from A2 neurons provide a route through which
interoceptive feedback from the body impacts not only hypothalamic functions but also emotional and cognitive processing
(21, 141, 211, 225).
The neuroanatomical and phenotypic features of A2 neurons
will first be considered in this review, followed by a summary
of evidence that A2 neurons provide a critical brain-body
interface linking emotional/cognitive events with physiological
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Rinaman L. Hindbrain noradrenergic A2 neurons: diverse roles in autonomic, endocrine, cognitive, and behavioral functions. Am J Physiol Regul
Integr Comp Physiol 300: R222–R235, 2011. First published October 20, 2010;
doi:10.1152/ajpregu.00556.2010.—Central noradrenergic (NA) signaling is
broadly implicated in behavioral and physiological processes related to attention,
arousal, motivation, learning and memory, and homeostasis. This review focuses on
the A2 cell group of NA neurons, located within the hindbrain dorsal vagal complex
(DVC). The intra-DVC location of A2 neurons supports their role in vagal
sensory-motor reflex arcs and visceral motor outflow. A2 neurons also are reciprocally connected with multiple brain stem, hypothalamic, and limbic forebrain
regions. The extra-DVC connections of A2 neurons provide a route through which
emotional and cognitive events can modulate visceral motor outflow and also a
route through which interoceptive feedback from the body can impact hypothalamic functions as well as emotional and cognitive processing. This review
considers some of the hallmark anatomical and chemical features of A2 neurons,
followed by presentation of evidence supporting a role for A2 neurons in modulating food intake, affective behavior, behavioral and physiological stress responses, emotional learning, and drug dependence. Increased knowledge about the
organization and function of the A2 cell group and the neural circuits in which A2
neurons participate should contribute to a better understanding of how the brain
orchestrates adaptive responses to the various threats and opportunities of life and
should further reveal the central underpinnings of stress-related physiological and
emotional dysregulation.
Review
HINDBRAIN NORADRENERGIC A2 NEURONS
distinguish these levels from the more rostral gustatory NST
(143). The visceral NST is a key component of the DVC,
which also includes the area postrema (AP) and dorsal motor
nucleus of the vagus. The DVC is a critical central node for
controlling hormonal and autonomic outflow, and relaying
interoceptive feedback from body to brain (201, 205, 206,
291). The AP and a significant portion of the medial NST
underlying the AP contain fenestrated capillaries, allowing
blood-borne factors (e.g., hormones, toxins, cytokines) to affect A2 and other neurons local to this region. Within the DVC,
AP neurons innervate the subjacent NST, and NST neurons
innervate other NST neurons as well as vagal preganglionic
parasympathetic neurons whose cell bodies occupy the dorsal
motor nucleus of the vagus and whose dendrites ramify widely
within the NST (239). All three components of the DVC also
receive extrinsic neural inputs from the periphery and brain,
described further, below.
Although the A2 cell group is centered within the visceral
NST, A2 neurons are not confined to cytoarchitecturallydistinct NST subnuclei. Instead, they form two bilaterally
symmetrical loose linear columns of medium-sized ovoid or
multipolar cells that extend rostrocaudally through the visceral
NST (232) (Fig. 1). A2 neurons are most prevalent within the
medial subnucleus of the NST at the rostrocaudal level of the
AP, but they also exist within the NST commissural subnucleus at the level of the AP and more caudally. Furthermore,
some A2 neurons are located within and just lateral to the
cytoarchitectural boundaries of the dorsal motor nucleus of
the vagus (232). The most caudal A2 neurons are located in
the upper cervical spinal cord, and the most rostral are
located rostral to the AP at the level of the caudal fourth
ventricle (Fig. 1). It should here be noted that the more rostral
A2 neurons are intermixed with PNMT-positive adrenergic
neurons of the C2 cell group (Figs. 1 and 2), which also are
TH- and DbH-positive. Many of the neuroanatomical and
functional studies cited in this review relied on anatomical
localization together with TH or DbH immunolabeling to
support, especially during stressful events that challenge bodily
homeostasis. This general theme will be supported by briefly
reviewing the involvement of A2 neurons in food intake,
affective behavior, stress responses, emotional learning, and
drug dependence. Most of the information reviewed in this
article was derived from studies using rats and, to a lesser
extent, mice; however, central NA circuits are highly conserved across mammalian species. Thus, understanding the
functional organization of the A2 cell group in rodents has
clinical relevance, and should contribute to a better understanding of stress-related physiological and emotional dysregulation
in humans.
Anatomical and Neurochemical Features
Location of A2 neurons. The A2 cell group is centered
within intermediate and caudal levels of the nucleus of the
solitary tract (NST) (Fig. 1), referred to as the visceral NST to
AJP-Regul Integr Comp Physiol • VOL
Fig. 2. Dual immunofluorescence labeling for DbH (red) and PNMT (green) in
a tissue section through the rat dorsomedial medulla (⬃13.3 mm caudal to
bregma) where neurons of the A2 and C2 cell groups intermingle. 4, fourth
ventricle.
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Fig. 1. Immunoperoxidase localization of dopamine-␤-hydroxylase (DbH; left)
and phenylethanolamine N-methyltransferase (PNMT; right ) within the caudal
dorsomedial medulla of an adult male Sprague-Dawley rat. Side-by-side panels
represent closely adjacent tissue sections. Top 4: caudal levels of the A2 cell
group (⬃14.6 mm caudal to bregma). Bottom 4: most rostral levels (⬃13.3 mm
caudal to bregma). DbH-positive neurons within the A2 cell group are
indicated by arrows. AP, area postrema; cc, central canal; DMV, dorsal motor
nucleus of the vagus; NST, nucleus of the solitary tract; 4, fourth ventricle.
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HINDBRAIN NORADRENERGIC A2 NEURONS
Extrinsic Inputs and Axonal Projections
Sensory inputs to A2 neurons. In addition to local axonal
inputs from the superjacent AP that are positioned to relay
blood-borne signals to A2 neurons (54, 118, 238), the A2
region of the visceral NST receives sensory feedback from the
cardiovascular, respiratory, and alimentary systems (119).
These visceral sensory inputs arrive predominantly via glutamatergic glossopharyngeal and vagal afferents whose central
axons converge in the solitary tract before synapsing with the
AJP-Regul Integr Comp Physiol • VOL
dendrites and somata of NST and vagal motor neurons (5, 14,
208, 246). In mice, ⬃90% of A2 neurons receive direct
synaptic input from visceral afferents in the solitary tract (6).
These glutamatergic inputs produce tightly synced, large-amplitude excitatory postsynaptic currents in A2 neurons, providing high-fidelity transmission of sensory afferent activity (6).
Other visceral and somatic sensory inputs are relayed to the A2
region of the NST from the spinal cord, trigeminal and related
nuclei, and reticular formation (5, 7, 71, 152, 153).
Given the diversity of sensory inputs received by A2 neurons, it is not surprising that they respond to a broad array of
interoceptive signals, including hormonal, osmotic, gastrointestinal, cardiovascular, respiratory, and inflammatory signals
(20, 23, 43, 45, 66, 77, 97, 112, 120, 167, 168, 201, 202, 207,
212, 213, 230). In these and many other studies, stimulusinduced A2 neuronal activation is characterized by immunocytochemical localization of the immediate-early gene product,
Fos, together with immunolabeling for TH or DbH. Increased
Fos immunolabeling alone cannot reveal the circuits through
which A2 neurons are recruited by a given stimulus or event,
but A2 neurons are consistently activated by treatments or
situations that present actual or anticipated threats to bodily
homeostasis. In many cases the relevant information is communicated to A2 neurons by visceral sensory afferents, but in
other cases A2 neurons appear to be recruited by descending
inputs from the hypothalamus and limbic forebrain (30, 67, 68,
137, 138). These inputs are reviewed in the following section.
Central inputs to A2 neurons. Retrograde and anterograde
tract-tracing studies have revealed a wide array of brain stem
and forebrain nuclei that project directly to the visceral NST
and may participate in recruitment of A2 neurons. As summarized in Table 1, these include various regions of the medullary, pontine, and mesencephalic reticular formation (13, 157,
166, 180); the cerebellar fastigial nucleus (180); the raphé
obscurus, pallidus, magnus, paragigantocellularis, and parapyramidal region (144, 180, 256); the laterodorsal tegmental
nucleus (180); the retrotrapezoid nucleus (220); the parabrachial nucleus and Kölliker-Fuse nucleus (130, 180); the periaqueductal gray (180); the hypothalamic tuberomammillary
nuclei (182); the hypothalamic arcuate nucleus (266, 295); the
PVN (100, 204, 228, 245, 266); the lateral hypothalamic area
(180, 266, 294); the median preoptic nucleus (180); the dorsomedial hypothalamus (287); the central nucleus of the amygdala (CeA) and anterolateral bed nucleus of the stria terminalis
(alBST) (116, 140, 180, 222, 266); the lateral septal nucleus
(180); and glutamatergic pyramidal neurons in the insular
cortex and in prelimbic and infralimbic regions of the medial
prefrontal cortex (266). All of these brain regions are logical
candidates for sources of direct input to A2 neurons, although
dual-labeling electron microscopy is necessary to confirm synaptic connectivity. The limited ultrastructural evidence that is
available indicates that at least a subset of A2 neurons receive
synaptic input from noncatecholaminergic neurons in the adjacent AP (118), and at least some A2 neurons receive glutamatergic inputs from the infralimbic region of the medial
prefrontal cortex (94). It also seems likely that A2 neurons are
among the catecholaminergic neurons within the visceral NST
that receive synaptic input from the CeA (189) and from
orexin-positive neurons in the lateral hypothalamus (17).
Axonal projections of A2 neurons. A2 neurons project locally within the DVC and medullary reticular formation, and
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identify and/or lesion A2 neurons; however, these criteria do
not allow A2 and C2 neurons to be distinguished within
visceral NST regions where they overlap. The extent to which
the connections and functions of these rostral A2/caudal C2
neurons are similar or unique remains largely unexplored.
Transmitter coexpression by A2 neurons. When considering
the functional role of A2 projection systems, it’s important to
keep in mind that these NA neurons release more than just NE
from their axon terminals and varicosities. In addition to TH
and DbH, A2 neurons express mRNA and/or are immunopositive for many additional signaling molecules. In rats, ⬃80%
of A2 neurons reportedly express mRNA for a homolog of the
vesicular glutamate transporter-2 (248), suggesting that these
neurons release glutamate along with NE. In addition, virtually
all A2 neurons are immunoreactive for prolactin-releasing
peptide (PrRP) (52). PrRP receptors are expressed within the
paraventricular nucleus of the hypothalamus (PVN) and other
brain regions targeted by A2 neurons (284), and there is
evidence that PrRP acts synergistically with NE to activate
hypophysiotropic corticotropin-releasing hormone (CRH) neurons at the apex of the hypothalamic-pituitary-adrenal (HPA)
axis (147, 261). Interestingly, the ratios of PrRP to NA biosynthetic enzymes in A2 neurons are modulated by estrogen
and stress (235), and A2 neurons express receptors for estrogen
and glucocorticoids (56, 101, 198, 243).
Regarding other peptides and phenotypic markers, subpopulations of A2 neurons are immunopositive for neuropeptide Y
(83, 233), nesfatin-1 (23), dynorphin (40), neurotensin (200),
and/or pituitary adenylate cyclase-activating polypeptide (61).
Conversely, A2 neurons apparently do not colocalize galanin
(136), somatostatin (226, 227), enkephalin (226), inhibin-␤
(226), glucagon-like peptide 1 (133, 203), or the enzyme
11-␤-hydroxysteroid dehydrogenase-2 (99), despite their close
anatomical proximity to NST neurons, which do express these
various phenotypic markers. A2 neurons also do not appear to
coexpress cocaine and amphetamine-related transcript, neurotensin, or cholecystokinin, in contrast to coexpression of these
peptides by PNMT-positive neurons of the partially overlapping C2 cell group (84, 122).
Receptor expression by A2 neurons. Neurons within the
A2 region of the visceral NST express receptor mRNA and
binding sites for a large number of neurotransmitters and
other signaling molecules, although confirmation of receptor
expression by identified A2 neurons is relatively limited.
The available data indicate that A2 neurons express ␣-2a
adrenergic receptors (154, 221) as well as receptors for
glutamate (6, 89), GABA (116), cannabinoids (38), CRH
(171), neuropeptide Y (288), leptin (80), glucocorticoids
(219), and estrogen (56, 198, 243). A2 neurons do not
express mineralocorticoid receptors (99).
Review
HINDBRAIN NORADRENERGIC A2 NEURONS
Table 1. Central connections of the A2 region of the dorsal
vagal complex
Central Connections
incidence of nonsynaptic NA varicosities in these regions is
much higher (15, 46, 82, 175, 187, 190). Thus, A2 neurons
may release their transmitter synaptically and in a paracrine
manner, requiring that NE and other costored transmitters must
diffuse short distances through the extracellular space to bind
to cognate receptors (cf. Ref. 190).
A subset of individual A2 neurons have axon collaterals that
innervate both the PVN as well as the CeA and/or alBST in rats
(16, 20, 185, 234). In addition, some A2 neurons project both
to brain stem autonomic regions and to limbic forebrain targets
(197). Interestingly, however, different brain stem autonomic
regions appear to be targeted by different sets of A2 neurons
(111), suggesting a higher degree of anatomical specificity for
brain stem projections vs. hypothalamic and limbic forebrain
projections of A2 neurons.
A2 axonal projections that ascend rostrally beyond the
medulla do so primarily within the ventral NA bundle (VNAB)
(4, 95, 156, 160, 231, 250, 276). It’s relevant to note here that
non-NA projections from the NST to the caudal ventrolateral
medulla (111) allow visceral signals to recruit NA neurons of
the A1 cell group (14, 111, 123, 260, 286), located at the same
rostrocaudal level as the more dorsally situated A2 cell group.
Some A1 and non-NA neurons within the ventrolateral medulla
project back to the DVC (157) to participate in vagal motor
outflow to the stomach (109, 110) and presumably other
visceral targets, but the axons of many A1 neurons join A2
projections within the VNAB (44, 230, 232). The extent to
which A1 and A2 projection targets are similar or distinct
remains ripe for investigation, although there is evidence that
they target phenotypically distinct neurons and subregions of
the PVN and supraoptic nuclei (195, 196, 232). In the absence
of specific evidence to discriminate between A1 and A2 neurons, a conservative approach dictates that projections and
functions ascribed to either cell group should be considered
Italicized ⫽ source of axonal input to the A2 region; Underlined ⫽ target of
A2 axonal projections; Bold ⴝ both a source of axonal input to the A2
region and a target of A2 axonal projections. Citations are provided in text.
comprise a subset of preautonomic NST neurons implicated in
vagal control of cardiovascular and digestive functions (77,
110, 146, 184, 218, 259). Dual-labeling retrograde tracing
studies indicate that identified A2 neurons also project to
multiple higher brain regions (201), as summarized in Table 1.
These regions include the parabrachial nucleus, locus coeruleus (LC) and peri-LC region, periaqueductal gray, ventral
tegmental area and retrorubral field, midline thalamic nuclei,
tuberomammillary nucleus, arcuate nucleus, dorsomedial nucleus of the hypothalamus, PVN (Fig. 3), lateral hypothalamic
area, median preoptic nucleus, subfornical organ, supraoptic
nucleus, CeA, alBST, substantia innominata, and nucleus accumbens (NAcc) (14, 46, 82, 96, 104, 105, 116, 121, 158,
199 –201, 232, 253, 254, 272).
Regarding the central targets of A2 axonal projections, it is
useful to know that synaptic junctions may not be the primary
release site for NE and other signaling molecules that are
synthesized by A2 neurons. TH- and DbH-positive NA terminals within the PVN and other brain regions targeted by A2
neurons have been observed to form classical type I and type
II synaptic inputs to postsynaptic structures; however, the
AJP-Regul Integr Comp Physiol • VOL
Fig. 3. Dual immunofluorescence labeling of anterogradely-transported
Phaseolus vulgaris leucoagglutinin (PhAL) neural tracer (green) and DbH
(red) identifying axons in the medial parvocellular (mp) and lateral magnocellular (lm) subregions of the paraventricular nucleus of the hypothalamus
(PVN). PhAL was microinjected iontophoretically into a portion of the A2
region in an adult male Sprague-Dawley rat 14 days before death (see Ref.
201).
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• Spinal cord, cranial nerves
Dorsal horn and lamina X
Glossopharyngeal and vagal sensory afferents (via solitary tract)
• Medulla, Pons, and Midbrain
Dorsal motor nucleus of the vagus
Nucleus ambiguous
Area postrema
Trigeminal and related nuclei
Medullary, pontine, mesencephalic reticular formation
Raphé obscurus, pallidus, magnus, paragigantocellularis, and
parapyramidal region
Locus coeruleus and peri-locus coeruleus region
Cerebellar fastigial nucleus
Parabrachial nucleus
Kölliker-Fuse nucleus
Laterodorsal tegmental nucleus
Ventral tegmental area
Retrorubral field
Retrotrapezoid nucleus
Periaqueductal gray
• Thalamus and hypothalamus
Midline thalamic nuclei
Tuberomammillary nucleus
Arcuate nucleus
Paraventricular nucleus
Lateral hypothalamic area
Dorsomedial nucleus
Median preoptic nucleus
Supraoptic nucleus
Subfornical organ
• Telencephalon
Central nucleus of the amygdala
Anterolateral bed nucleus of the stria terminalis
Substantia innominata
Nucleus accumbens
Lateral septal nucleus
Insular cortex
Medial prefrontal cortex
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HINDBRAIN NORADRENERGIC A2 NEURONS
likely shared by the other. The following sections review
several examples of functions in which A2 neurons have been
implicated, but the reader should consider that A1 neurons also
are likely to be involved in at least a subset of these functions.
A2 Neurons and Food Intake
Fig. 4. Dual immunoperoxidase labeling of cFos protein (blue/black nuclear
label) and cytoplasmic DbH (brown label) within the caudal visceral NST. This
section was taken from a rat perfused with fixative 60 min after intraperitoneal
administration of cholecystokinin octapeptide (100 ␮g/kg body wt) to stimulate vagal sensory inputs to the NST. Arrows point out activated (i.e.,
cFos-positive) A2 neurons (see Refs. 210 and 213).
AJP-Regul Integr Comp Physiol • VOL
The trajectory and targets of NA fibers within the VNAB are
distinct from those of the dorsal NA bundle, which originates
from neurons within the pontine LC (A4 and A6 cell group
regions). The vast majority of publications considering the role
of central NA signaling in stress, cognition, and affective
processes emphasize the LC and its projection targets, and
either disregard or downplay the contributions of A2 neurons
and their projections. The LC is assumed to be the principle
source of the central NA signaling that underlies not only
behavioral arousal but also HPA axis hyperactivity associated
with stress (48 –50, 289) as well as the dysregulated NA
transmission that contributes to diverse models of stress vulnerability and affective disorders (9, 51). However, NA inputs
to the PVN, CeA, alBST, and NAcc that are critical for
hormonal, behavioral, and affective responses to physiologically significant events arise from the caudal medullary A1 and
A2 cell groups, with relatively little input from the LC (70,
230, 232). When clinical researchers measure growth hormone
responses to an adrenergic agent (e.g., clonidine) to indirectly
assess brain NA signaling in individuals with stress-related
affective disorders (1, 72, 241, 242), it is primarily NA signaling by medullary A1/A2 inputs to the hypothalamus that is
being assessed (47, 81, 165, 282), not LC inputs. Furthermore,
results from a recent retrograde tracing and VNAB lesion study
indicate that the majority of NA inputs to reward-related
midbrain dopamine neurons arise from the caudal medulla,
including the A2 cell group (151). Conversely, A2 neurons do
not innervate most of the brain regions that are innervated by
the LC, including the olfactory bulb, cerebral cortex, hippocampus, medial BST, basolateral amygdala, most thalamic
nuclei, and the cerebellum (163). Moreover, NA signaling
within LC-innervated brain regions can produce behavioral
effects that are quite different from those produced by NA
signaling within A2-innervated regions. For example, ␣-adrenergic receptor activation underlies positively motivated exploratory/approach behavior in cortical and subcortical regions
innervated by the LC, but underlies stress reactions with
behavioral inhibition in regions innervated by the A2 cell
group (29, 41, 42, 69, 164, 192, 215, 247, 277, 278).
Neurons within the A2 region of the visceral NST project to
the LC (201), but project more densely to the peri-LC region
where the dendrites of LC neurons cluster, synapsing there on
TH-positive dendrites (264, 265). As mentioned previously,
A2 neurons coexpress PrRP immunolabeling (52), and the LC
contains PrRP-positive fibers and terminals as well as the
receptor (UHR-1) for PrRP (284). While the evidence is
indirect, these findings indicate that A2 neurons may provide
modulatory control over NA neurons within the LC, thereby
indirectly modifying NA signaling within cortical, hippocampal, amygdalar, thalamic, and cerebellar targets of the LC.
Interestingly, despite the LC-centered focus of most research
on the role of NA brain systems in affective behavior, researchers have not been able to demonstrate unequivocally the
necessity of LC neurons in fear, anxiety, or depressive-like
behavior (114). Indeed, LC lesions appear to increase, rather
than decrease, novelty-induced fear and anxiety in rats (103,
148). Moreover, in one study, LC lesions increased the antidepressant-like effect of reboxetine (a NE reuptake inhibitor),
whereas VNAB lesions abolished the drug’s antidepressant
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Central NA signaling pathways, including those that arise
from A2 neurons, appear to be essential for inhibiting or
stimulating food intake under different conditions (2, 62, 142,
156, 170, 203, 209, 214, 216). It seems likely that different
subpopulations of A2 neurons with distinct axonal projections
are recruited by signals that increase or decrease food intake,
perhaps because different subpopulations target different brain
regions, and/or because different combinations of adrenergic
receptors are expressed within those regions (277). Interestingly, A2 neurons in rats appear to be activated in every
experimental situation in which food intake is inhibited, including normal satiety (37, 115, 203, 207, 262). A2 neurons are
recruited in a graded manner in rats after voluntary food intake,
such that larger meals activate larger numbers of A2 neurons
(207). Not only are A2 neurons robustly activated in rats after
systemic administration of cholecystokinin octapeptide (210,
213) (Fig. 4), they are necessary for the ability of cholecystokinin to inhibit food intake and to activate neurons within the
hypothalamic PVN (203). A2 neurons also contribute importantly to the hypophagic effect of lithium chloride (209). Food
intake is reduced in rats after central administration of PrRP
(134) or nesfatin-1 (174), each of which is coexpressed by A2
neurons (23, 52). A2 neurons are robustly activated by experimental treatments or situations that produce hypophagia or
anorexia as a part of the depressive-like sickness behavior
accompanying systemic infection or visceral malaise (23, 96 –
98, 201, 202). These conditions also are associated with inhibition of vagally mediated gastric emptying, which likely
underlies or contributes to hypophagia (37, 202, 203). The
potential involvement of A2 neurons in other aspects of food
intake and regulation of body energy homeostasis are the
subject of a recent review (201).
A2 Neurons, the LC, and Affective Behavior
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HINDBRAIN NORADRENERGIC A2 NEURONS
effects (53). These results invite a continued expansion of
research into the role of A2 neurons and their central projections in affective behavior.
A2 Neurons and Stress Responses
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mpPVN markedly attenuate CRH neuronal responses to interoceptive signals (20, 90, 137, 203, 209, 215, 234). Conversely,
chronic stress sensitizes HPA axis responses to central NA
(183) and increases the density of glutamatergic and NA
synaptic inputs to CRH-positive neurons, evidence for enhanced signaling capacity (86). The authors of the latter study
did not consider whether the increased glutamatergic and NA
inputs arise from the same A2 neurons, but this seems likely.
Magnocellular oxytocin neurons and parvocellular thyrotropin releasing hormone-positive mpPVN neurons also receive synaptic input from the A2 cell group (57, 58, 93, 240,
283). In addition, nonendocrine gastric preautonomic neurons
in the PVN receive direct synaptic input from NA nerve
terminals that include inputs from A2 neurons (15). Preautonomic PVN neurons project to hindbrain and spinal centers to
control autonomic motor outflow to the gastrointestinal tract
and other organ systems (16, 87, 204, 251) to thereby shape
visceral responses to emotive stimuli and stress (228, 292).
alBST. The anterolateral group of BST nuclei (alBST) includes the juxtacapsular, oval, rhomboid, fusiform, and subcommissural zone (75). The alBST is connected with autonomicrelated portions of the hypothalamus and caudal medulla, and
receives an extremely dense NA innervation that arises from
A2 (and A1) neurons, but not from the LC (11, 25, 69, 74, 75,
186 –188, 252, 275). NA acts within the alBST to modulate
behavioral, hormonal, and conditioned emotional responses to
stress (41, 179), including, for example, responses to the stress
of precipitated opiate withdrawal (11, 78). The alBST also
receives input from the hippocampus and prefrontal cortex, and
has abundant projections to the mpPVN (74). At least a subset
of A2 neurons that innervate the alBST have axon collaterals
that target the mpPVN (16, 20), and NA signaling within the
alBST contributes to stress-induced HPA axis activation (88,
135). Certain aspects of BST-mediated anxiety responses appear to depend on CRH inputs from the amygdala (63, 270,
271) with which the alBST is strongly and reciprocally connected (73). Blockade of NA signaling in the ventral alBST
reduces immobilization stress-induced anxiety in the elevatedplus maze and attenuates immobilization stress-induced increases in plasma ACTH, but the same pharmacological manipulation has no effect to attenuate stress responses in a
subsequent social interaction test (41); the reverse is true for
similar manipulations in the CeA (42). These findings suggest
that A2 inputs to the alBST and CeA are involved in different
specific components of stress and anxiety responses (cf. Ref.
244).
CeA. The CeA, like the alBST, is a subcortical limbic
structure characterized by its extensive connections with the
hypothalamus and with brain stem viscerosensory and autonomic control nuclei. As part of the striatal amygdala, CeA
neurons are primarily GABAergic and coexpress CRH, similar
to neurons in the alBST (73, 249). Although NA inputs to the
CeA are significantly less dense than NA inputs to the mpPVN
and alBST (16, 167, 169), NA signaling within the CeA
modulates behavioral responses to stressful events, including
fear, anxiety, and avoidance behavior (64, 125). NA signaling
in the CeA increases during precipitated opiate withdrawal and
contributes to the negative affective (i.e., aversive) consequences of withdrawal (273), similar to increased NA signaling
and implication in aversive effects within the alBST (11). A2
neurons that project to the CeA are activated in rats after
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Stressors are stimuli or events that challenge (or are perceived to challenge) bodily homeostasis and well-being. Signals generated by stressors may initially arrive from the environment (e.g., visual or olfactory signals), or may arise from
within the body (e.g., cardiovascular or gastrointestinal signals). Physiological and behavioral responses to stressful stimuli are the product of interactions among multiple brain regions
(107, 108). However, three interconnected regions of the hypothalamus and so-called extended amygdala are especially
important, and have been the subject of extensive experimental
attention: the medial parvocellular PVN (mpPVN), CeA, and
alBST. Each region contains CRH neurons that receive synaptic input from NA terminals arising primarily or exclusively
from the A2 (and A1) cell groups, and CRH neuronal activity
within each region is closely regulated by these inputs (4, 10,
65, 74, 78, 79, 124, 126 –128, 139, 181, 186, 191, 192, 244).
A2 neurons express glucocorticoid receptors (101), and central
adrenergic and CRH receptors are regulated by glucocorticoids, which are known to affect NE synthesis and turnover
throughout the brain. NA-CRH signaling pathways are viewed
as part of a central adrenal steroid-sensitive network that tunes
physiological and behavioral responses during conditions of
acute or chronic stress (106). In general, and as discussed
further, below, NA signaling is pivotal in facilitating HPA axis
and behavioral responses to stress, and can modulate unconditioned and conditioned behavioral responses to stressful and
emotional stimuli, including stimuli that evoke fear and anxiety
(223). Enhanced NA transmission in human subjects is associated with enhanced HPA axis responses to stress, which may
contribute to the psychopathology of depression, anxiety, and
other affective disorders (128). The hindbrain A2 cell group
appears to be a fundamental player in these central mechanisms, as summarized in the following sections.
PVN. Most hypothalamic NA input arrives from medullary
NA cell groups. A2 neurons appear to selectively target the
mpPVN (55, 230, 232), although axonal projections from the
A2 region to the lateral magnocellular PVN also are common
(see Fig. 3 and discussion in the following section). The
necessity of NA inputs for HPA axis responses to stress
appears to vary across different types of stress stimuli (20, 66,
137, 224, 229), but NA input to the mpPVN, arriving via the
VNAB, provides the major known stimulus for CRH synthesis
and release (65, 181, 192, 250, 283). CRH is the principal and
obligate hypophysiotropic peptide driving the pituitary-adrenal
axis under basal conditions and in response to homeostatic
challenge (192, 274).
In rats, stressful stimuli that activate A2 neurons and recruit
the HPA axis also activate hypothalamic oxytocin neurons
(177, 178, 206, 263, 267–269). CRH and oxytocin neurons
receive direct synaptic input from NA terminals, and NA
inputs increase CRH and oxytocin excitability (3, 4, 22, 113,
155, 192, 195, 196, 217, 285). In late pregnancy and during
lactation, oxytocin and HPA axis responses to stressors are
attenuated by mechanisms that reduce NA tone within the PVN
(26 –28, 76, 257, 258). Lesions that decrease NA input to the
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HINDBRAIN NORADRENERGIC A2 NEURONS
gastric vagal sensory stimulation with exogenous cholecystokinin (169) or systemic immune challenge (97), and also are
activated by emotionally salient exteroceptive stimuli, such as
exposure to a predator odor (168).
A2 Neurons and Emotional Learning
A2 Neurons in Drug Use and Dependence
Central neural adaptations elicited by exposure to addictive
drugs are not limited to brain reward circuits, but also are
manifest in stress-related pathways that are implicated in addiction (173). For example, rats dependent on morphine display increased enzymatic activity of A2 neurons and increased
NA turnover within the PVN, concurrent with enhanced activity of the HPA axis that depends on NA input (18, 92, 131, 132,
172). In addition, medullary NA inputs to the alBST, CeA, and
NAcc are critical for the aversiveness of acute opiate withdrawal, and for stress-induced relapse of drug seeking for
opiates, cocaine, ethanol, and nicotine (11, 24, 36, 69, 78, 145,
244, 293). NA inputs to the alBST trigger GABAergic inhibition of alBST neurons that project to the ventral tegmental
area, which likely contributes to the inhibition of DA neurons
that occurs during opiate withdrawal (78). Thus, common
inputs to the hypothalamus and limbic forebrain from the A2
cell group could be a critical factor linking these brain areas in
circuits that underlie drug use and dependence (102, 236, 237).
Even 5 wk after opiate withdrawal, neurons within these limbic
forebrain regions remain hypersensitive to drug-related cues
and stress, which may drive behavior away from the pursuit of
AJP-Regul Integr Comp Physiol • VOL
Conclusion
The diverse challenges and opportunities of life elicit a
constellation of autonomic, endocrine, cognitive, and behavioral responses, and A2 neurons are poised to contribute to the
central coordination and modulation of these responses. As
reviewed in this article, feedback regarding the body’s physiological state is relayed by A2 neurons to multiple regions of
the brain stem, hypothalamus, and limbic forebrain. The A2
cell group is best defined by its afferent and efferent connections within a complex neural network that extends from the
spinal cord to the cortex. The available evidence indicates that
by virtue of their central axonal projections, this relatively
small group of caudal medullary neurons can modulate ongoing and future physiological processes and behaviors, and may
also contribute to the affective, contextual, and cognitive attributes of experience that depend on interoceptive feedback
from body to brain (19, 60, 149, 194, 255).
GRANTS
This manuscript was prepared with the support of National Institute of
Mental Health Grants MH-59911 and MH-081817.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
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